Low Systemic Clearance Research Articles

Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity

The major drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 is genetically conserved. One outlier of Brazilian descent was found in a clinical pharmacokinetic trial exhibiting a 6-fold higher exposure than expected to an investigational drug, shown to be a CYP3A4 substrate. We aimed to investigate the genetic background of this finding. The allelic variant of the CYP3A4 gene present in the outlier was sequenced, and the corresponding complementary deoxyribonucleic acid was expressed in yeast and human embryonic kidney cells. The outlier was phenotyped by use of intravenous administration of 1 mg midazolam. Analysis of phenotype and genotype correlation was carried out. The prevalence of the new allele was screened for in a white population. We identified a subject who heterozygously carried a novel CYP3A4 allele, named CYP3A4*20, with a premature stop codon yielding a truncated protein. Heterologous expression revealed that the CYP3A4.20 enzyme does not incorporate heme and thus is devoid of catalytic activity. CYP3A phenotyping in vivo showed that CYP3A4*20 exhibits a clear genotype-phenotype correlation, demonstrated by the subject's low systemic midazolam clearance (2.99 mL x min(-1) x kg(-1)). Genotyping of a white German population (n = 428) and relatives of the subject, as well as a review of published CYP3A4 sequencing data, suggests that CYP3A4*20 is a rare variant allele (<0.06% in white subjects). CYP3A4*20 represents the first CYP3A4 allele to be identified that has been shown to be devoid of functional activity. It causes an intermediate CYP3A4 metabolizer phenotype in a heterozygous carrier. Subjects of this genotype might be susceptible to side effects during drug therapy with substrates or inhibitors of CYP3A4.

Effect of the genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers

Our objective was to investigate the effect of the uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism on the pharmacokinetics and pharmacodynamics of lorazepam in basal, inhibited, and induced metabolic states in healthy normal volunteers. Twenty-four healthy subjects were enrolled and grouped into UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic and pharmacodynamic profiles of intravenous lorazepam were characterized before and after inhibition with 600 mg valproate once daily for 4 days and after induction with rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 10 days between. The plasma concentrations of lorazepam and lorazepam glucuronide were analyzed before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours after lorazepam administration by liquid chromatography-tandem mass spectrometry. Visual analog scale assessments and psychomotor coordination tests were administered before and up to 12 hours after drug administration. The UGT2B15*2/*2 group showed 0.58-fold (95% confidence interval, 0.43-0.72; P < .0001) lower systemic clearance during the basal state and 1.37-fold (95% confidence interval, 1.05-1.88; P = .037) higher area under the visual analog scale-time curve during the induced state compared with the UGT2B15*1/*1 group. The mean systemic clearance of lorazepam decreased by 20% in the inhibited state and increased by 140% in the induced state. During the inhibited or induced state, absolute values of clearance were consistently lower in the *2/*2 group, but the percent changes from baseline did not differ significantly by genotype. Our results suggest that the UGT2B15*2 polymorphism is a major determinant of interindividual variability with respect to the pharmacokinetics and pharmacodynamics of lorazepam.

Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1)

Fexofenadine pharmacokinetics are associated with a polymorphism of the <i>SLCO1B1</i> gene (encoding OATP1B1)

Pharmacokinetics, Pharmacodynamics and Drug Interaction Potential of Enfuvirtide

Enfuvirtide, the first fusion inhibitor approved for the treatment of HIV-1 infection, is a synthetic peptide that binds to HIV-1 glycoprotein 41, blocking the fusion of viral and cellular membranes. When administered subcutaneously at the recommended dose of 90 mg twice daily with optimised background antiretroviral therapy, enfuvirtide significantly reduces plasma HIV-1 RNA levels up to 48 weeks compared with optimised background therapy alone. Enfuvirtide exhibits a small volume of distribution (5.48 L), low systemic clearance (1.4 L/h) and high plasma protein binding (92%). Less than 17% of enfuvirtide is converted to a minimally active deaminated form of the parent drug. Both enfuvirtide and its metabolite are primarily eliminated via catabolism to amino acid residues. Following subcutaneous administration, enfuvirtide is almost completely absorbed, and exposure increases almost linearly with dose over the range 45-180 mg. When administered at the recommended dose in adults, subcutaneous absorption is slow and protracted, resulting in relatively flat steady-state plasma concentration-time profiles. Bioavailability is high (84.3%) and the elimination half-life (3.8 hours) supports twice-daily administration. Comparable absorption was observed from three different anatomical injection sites. The pharmacokinetic-pharmacodynamic relationship indicates that the recommended dose, in combination with other active antiretrovirals, is optimal. Enfuvirtide clearance is influenced to a small extent by sex and bodyweight but this does not necessitate dosage adjustment. In vitro and in vivo studies indicate that enfuvirtide has a low potential to interact with concomitantly administered drugs. Enfuvirtide did not influence concentrations of drugs metabolised by cytochrome P450 (CYP) 3A4, CYP2D6 or N-acetyltransferase, and had only minimal effects on those metabolised by CYP1A2, CYP2E1 or CYP2C19. Coadministration of ritonavir, ritonavir-boosted saquinavir or rifampicin (rifampin) did not result in clinically significant changes in enfuvirtide pharmacokinetics. In HIV-1-infected paediatric patients, subcutaneous dosages based on bodyweight (2 mg/kg twice daily) produce pharmacokinetics broadly similar to those observed in adults administered 90 mg twice daily.

Use of Photoaffinity Labeling and Site-directed Mutagenesis for Identification of the Key Residue Responsible for Extraordinarily High Affinity Binding of UCN-01 in Human α1-Acid Glycoprotein

7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor anticancer drug currently undergoing a phase II clinical trial. The low distribution volumes and systemic clearance of UCN-01 in human patients have been found to be caused in part by its extraordinarily high affinity binding to human alpha1-acid glycoprotein (hAGP). In the present study, we photolabeled hAGP with [3H]UCN-01 without further chemical modification. The photolabeling specificity of [3H]UCN-01 was confirmed by findings in which other hAGP binding ligands inhibited formation of covalent bonds between hAGP and [3H]UCN-01. The amino acid sequence of the photolabeled peptide was concluded to be SDVVYTDXK, corresponding to residues Ser-153 to Lys-161 of hAGP. No PTH derivatives were detected at the 8th cycle, which corresponded to the 160th Trp residue. This strongly implies that Trp-160 was photolabeled by [3H]UCN-01. Three recombinant hAGP mutants (W25A, W122A, and W160A) and wild-type recombinant hAGP were photolabeled by [3H]UCN-01. Only mutant W160A showed a marked decrease in the extent of photoincorporation. These results strongly suggest that Trp-160 plays a prominent role in the high affinity binding of [3H]UCN-01 to hAGP. A docking model of UCN-01 and hAGP around Trp-160 provided further details of the binding site topology.

Influence of C6 and CNS1 Brain Tumors on Methotrexate Pharmacokinetics in Plasma and Brain Tissue

Comparison of the influence of two different brain tumors (C6 and CNS1 glioma) on methotrexate (MTX) disposition in plasma, brain, and tumor tissue extracellular fluid (ECF). Serial collection of plasma samples and brain ECF dialysates after i.v. bolus administration of MTX (50 mg kg(-1)) for 4 h. Quantitation of MTX concentrations by HPLC-UV. Histological studies revealed a 3-fold higher number of blood vessels in CNS1 than in C6 tumor tissue. In vivo recoveries (reverse dialysis) were significantly different in tumor tissue (C6: 8.0 +/- 3.8%; CNS1: 4.9 +/- 2.5%), and in the contralateral hemisphere (C6: 6.0 +/- 4.0%; CNS1: 3.9 +/- 2.5%) between the two tumors. Area under the concentration-time curve (AUC) in plasma was 30% higher in CNS1 than in C6 due to a lower systemic clearance. Maximum MTX levels in brain tumor ECF were significantly higher in CNS1 than in C6, and decreased faster in CNS1 than in C6 tumor-bearing rats. Penetration in tumor ECF (AUC(ECF)/AUC(Plasma) ratio) was similar in CNS1 and C6. MTX concentrations in contralateral hemisphere were significantly lower than in tumor tissue and dependent on tumor model. C6 and CNS1 brain tumors have a distinct yet highly variable impact on MTX penetration in brain and brain tumor ECF.

A lipophilic paclitaxel derivative incorporated in a lipid emulsion for parenteral administration

Paclitaxel is one of the most effective and most widely-used anti-cancer agents. However, paclitaxel is difficult to formulate for parenteral administration because of its low aqueous solubility and Cremophor EL, the excipient used for its formulation, has been shown to cause serious side effects. This study reports an alternative administration vehicle involving a lipophilic paclitaxel derivative, paclitaxel oleate, incorporated in the core of a nano-size sterically stabilized oil-in-water (o/w) lipid emulsion. This lipid emulsion, with a particle size of 50 nm, has many favourable properties such as drug-carrier like biocompatibility, physical stability and ease of preparation. When paclitaxel in Cremophor EL/ethanol and paclitaxel oleate in emulsion were incubated with plasma a greater proportion of paclitaxel was found in the lipoprotein pool when formulated as paclitaxel oleate in a lipid emulsion compared to unesterified paclitaxel. The paclitaxel prodrug, paclitaxel oleate, demonstrated cytotoxic activity against cultured HeLa cells and with a marked increase in activity with incubation time. The 50% inhibition (IC50) was calculated to be 5500, 500, 150, and 100 nM for 24, 48, 72, and 96 h, respectively. Pharmacokinetic data, obtained with rabbits, showed significantly greater AUC, higher Cmax, lower systemic clearance and lower Vss when paclitaxel was formulated as an oleate prodrug in a lipid emulsion than when formulated in Cremophor EL/ethanol. The formulated emulsion may be clinically useful not only for eliminating toxic effects of Cremophor EL but also for improvement of the pharmacokinetic parameters of paclitaxel.

Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin

Bosentan is the first competitive antagonist at endothelin‐A and ‐B receptors that reached the clinic. Endothelin receptor antagonists display a wide spectrum of potential indications. The main indications for which bosentan is currently investigated are pulmonary arterial hypertension and chronic heart failure. Bosentan has a low systemic plasma clearance of approximately 12 l h−1 and a volume of distribution of approximately 0.5 l kg−1. In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP)2C9 and 3A4. The present interaction study was conducted to investigate the mutual pharmacokinetic interactions between bosentan and simvastatin, a substrate of CYP3A4. Inactive simvastatin (lactone form) is biotransformed into the active metabolite β‐hydroxyacid simvastatin. Nine healthy male subjects (age range 24–25 years) were treated in a three‐period randomized crossover study with A) bosentan 125 mg twice daily for 5.5 days; B) simvastatin 40 mg once a day for 6 days; C) bosentan 125 mg twice daily and simvastatin 40 mg once a day for 5.5 and 6 days, respectively. Steady‐state conditions of bosentan and its three identified metabolites were attained by day 4 of treatment, both in the absence and presence of simvastatin co‐administration. In total, the plasma concentrations of the bosentan metabolites were approximately 20% of those of bosentan. Ro 48‐5033, which is a pharmacologically active metabolite, showed an exposure, which was approximately 12% of that to bosentan. The pharmacokinetic parameters (geometric mean with 95% confidence intervals) of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: bosentan values for Cmax in treatment A and C 1006 (768–1318) and 1118 (872–1434) ng ml−1, respectively, and for AUC(0, τ) 4586 (3719–5656) and 4928 (3945–6156) ng ml−1 h, respectively. In contrast, concomitant administration of bosentan resulted in a decreased exposure to simvastatin and β‐hydroxyacid simvastatin. Cmax and AUC(0, τ) values of simvastatin in treatments B and C were 12.9 (8.1–20.5) and 10.7 (7.2–15.9) ng ml−1 and 30.5 (23.1–40.2) and 20.0 (15.9–25.1) ng ml−1 h, respectively. The values for β‐hydroxyacid simvastatin were 7.3 (5.4–9.7) and 6.0 (4.2–8.7) ng ml−1 and 43.0 (32.1–57.8) and 23.4 (16.7–32.6) ng ml−1 h for Cmax and AUC(0, τ) in treatments B and C, respectively. The decrease in exposure to simvastatin and β‐hydroxyacid simvastatin (34 and 46%, respectively) was statistically significant (P&lt;0.05). A trend for a higher incidence of adverse events was observed when bosentan and simvastatin were administered concomitantly, with headache the most frequently reported adverse event. There were no clinically relevant treatment‐related changes in vital signs, ECG or clinical laboratory parameters.In conclusion, the influence of bosentan on the pharmacokinetics of simvastatin and its metabolite is in accordance with bosentan's enzyme inducing properties. The possibility of reduced efficacy of simvastatin should be considered when administered concomitantly with bosentan.

CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5'-promoter region polymorphism.

Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability. Possible differences in CYP3A activity were investigated in European American and African American men with the use of midazolam as an in vivo probe. Midazolam was simultaneously administered intravenously (1 mg, [15N3]-labeled) and orally (2 mg, unlabeled in capsule form) to 15 young healthy European American men and a similar group of men of African American descent. Plasma concentration-time curves were measured. The subjects were subsequently genotyped with respect to the CYP3A4*B1 polymorphism (A-290G) in the 5'-promoter (nifedipine-specific element) region. The oral bioavailability of midazolam was about equally determined by intestinal and hepatic extraction with CYP3A activity at the former site exhibiting greater variability. Oral bioavailability was related to intestinal metabolism (r = 0.98), whereas hepatic CYP3A activity contributed little to the interindividual variability (r = 0.03). A lower systemic clearance (265+/-54 versus 310+/-56 mL/min; P = .04), but not oral clearance, was observed in African Americans. With one exception, the African Americans possessed a variant CYP3A4*1B allele (4 heterozygotes A/G and 10 homozygote G/G), whereas all of the European Americans were wild-type homozygotes (A/A). Hepatic CYP3A activity and the systemic clearance of midazolam were about 30% lower in G/G homozygotes than in A/A homozygotes (252+/-53 versus 310+/-54 mL/min; P = .02), and a gene-dose effect was present (P = .01). There was no genotype/phenotype relationship with respect to the oral clearance of midazolam. Comparison of CYP3A activity between populations is complicated by frequency distribution differences in the regulatory CYP3A4*1B polymorphism and lower hepatic CYP3A activity associated with the variant allele. However, this reduction is modest; therefore no major and clinically important difference in CYP3A activity is present between Americans of African or European descent.

Clinical pharmacokinetics of 2'-deoxy-2'-methylidenecytidine (DMDC), a deoxycytidine analogue antineoplastic agent.

This article reviews the clinical pharmacokinetics of a deoxycytidine analogue of cytarabine, 2'-deoxy-2'-methylidenecytidine (DMDC). DMDC belongs to the antimetabolite class of anticancer drugs and is phosphorylated into its active, triphosphate, form within the tumour cell. Cancer cell death appears to be a result of the impairment of DNA synthesis by the triphosphate form. DMDC undergoes deamination to the inactive 2'-deoxy-2'-methylideneuridine (DMDU), its main plasma metabolite. Following intravenous administration at 30 to 450 mg/m2, DMDC has low systemic clearance (10 to 15 L/h/m2), moderate volume of distribution (nominally similar to total body water) and a short elimination half-life of between 2 and 6 hours. Renal clearance of DMDC accounts for approximately 30 to 50% of total clearance. Following oral administration of DMDC at 12 to 50 mg/m2, mean maximum DMDC plasma concentrations are within the 100 to 400 microg/L range and are generally reached within 2 hours. Oral bioavailability of DMDC is in the order of 40%, largely as a result of first-pass metabolism in the gut and liver. This first-pass effect results in considerable interpatient variability in systemic exposure to DMDC after oral administration. The systemic availability of DMDC is proportional to the administered dose and, although there was evidence that systemic exposure to DMDC decreased on repeated administration, there are no excessive time-dependent changes in systemic exposure to DMDC. Following oral administration, DMDC is metabolised in the gut wall and liver by deamination to DMDU. The kidneys eliminate DMDC and DMDU, with up to 50% of the administered dose recovered in urine, on average, as parent drug and metabolite. Dose escalation to the maximum tolerated dose was facilitated by a pharmacokinetically guided dose escalation strategy. DMDC has shown activity in non-small-cell lung cancer and colorectal cancers following oral administration. Several tumour responses are observed at the highest doses of DMDC, indicating a possible dose-response relationship with this drug. The main clinical adverse event of DMDC therapy is myelotoxicity. The haematological toxicity of DMDC was schedule dependent; twice daily administration was associated with greater toxic effects than a once daily regimen. A pharmacokinetic-pharmacodynamic model characterised the relationship between plasma DMDC concentrations and the time-dissociated toxicity. This model-dependent approach may be used to predict the consequences of as-yet-untested therapy as well as relating acceptable risks of haematological toxicity to target drug exposure.

Altered disposition of repeated nicotine doses in rats immunized against nicotine.

Active immunization of rats against nicotine reduces the distribution of a single intravenous dose of nicotine to brain. The current study examined the effects of immunization on the distribution of repeated doses of nicotine, and on estimates of nicotine pharmacokinetic parameters. Groups of rats received five repeated doses of nicotine over 80 min (total dose equivalent to the nicotine intake from one, three or 10 cigarettes in a human). The serum nicotine concentration in immunized rats was 160-430% higher than controls after the fifth dose, demonstrating binding of nicotine to antibody. Brain nicotine concentration in immunized rats was reduced by 30-46%. The reduction in distribution of nicotine to brain correlated with the serum hapten-specific antibody concentration, the percentage of nicotine bound in serum, and with the unbound nicotine concentration in serum. In immunized rats, nicotine had a smaller steady state volume of distribution, lower systemic clearance, and longer terminal half-life than in controls. These data demonstrate that immunization against nicotine reduces nicotine distribution to brain, even after multiple nicotine doses at rates approximating heavy cigarette smoking. Whether this reduction in nicotine distribution is large enough to alter nicotine's physiological or behavioral effects remains to be studied.

Clinical pharmacokinetics of vinorelbine.

Vinorelbine (5'-noranhydrovinblastine) is a recently developed semisynthetic anticancer drug which belongs to the Catharanthus alkaloid family. Its mechanism of action is only partially known but it is assumed that it acts, like vinblastine and vincristine, as an antimicrotubule agent arresting cell division in mitosis. Clinically, vinorelbine has mainly shown activity in the treatment of advanced non-small-cell lung cancer and the treatment of metastatic breast cancer. Early pharmacokinetic data were obtained with radioactive assays (radio-immunoassay or 3H-labelled vinorelbine), then with more selective high performance liquid chromatographic techniques. Vinorelbine is usually administered intravenously but there has also been some experimentation with an oral formulation. The bioavailability of a liquid filled gelatin capsule ranges between 12 and 59% with a mean value of 27% [standard deviation (SD) 12%]. Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. In vitro, vinorelbine is mainly distributed into the blood cells, especially platelets (78%) and lymphocytes (4.8%) The unbound blood fraction is around 2%. In lung tissue vinorelbine concentrations are much higher than in serum, by up to 300-fold 3 hours after administration. Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. Urinary excretion of vinorelbine is low, accounting for less than 20% of the dose. Faecal elimination has been demonstrated in 2 patients who were administered 3H-labelled vinorelbine; the amount of radioactivity recovered in the faeces was 33.9 and 58.4% for the 2 patients, respectively. The pharmacokinetic profile of vinorelbine is often described as a 3-compartment model characterised by a long terminal half-life (t1/2) that varies between 20 and 40 hours and a large apparent volume of distribution (Vd) of around 70 L/kg. Systemic clearance ranges between 72.54 and 89.46 L/h (1209 and 1491 ml/min) when determined by high performance liquid chromatography and is higher than that reported by radioimmunoassay [46.2 L/h (770 ml/min)]. This could be due to the greater specificity of the chromatographic method. Vinorelbine has been administered by continuous intravenous infusion over 4 days. Steady-state was reached and the concentrations obtained were above the in vitro IC50 (concentration of drug causing 50% inhibition). The effect of liver disease on vinorelbine pharmacokinetics has been studied in patients with breast cancer. Patients with massive secondary liver disease had a lower systemic clearance than those who have no liver disease or a lesser invasion. In children, vinorelbine seems to display a shorter t1/2 (14.7 hours) than that found in adults. In addition, the systemic clearance is highly variable [from 12 to 93.96 L/h/m2 (200 to 1566 ml/min/m2)]. Vinorelbine is often co-administered with cisplatin in the treatment of advanced non-small-cell lung cancer. The disposition of the alkaloid is not altered by concurrent administration of cisplatin.

Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects

The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca. 1101); the apparent terminal half-life in plasma was ca. 8 h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (less than 10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non-specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.

Phmacodynamics and pharmacokinetics of carprofen, a non‐steroidal anti‐inflammatory drug, in healthy cows and cows with Escherichia coli endotoxin‐induced mastitis

The pharmacodynamics of carprofen and its pharmacokinetics in plasma and milk of healthy cows and cows with endotoxin-induced mastitis were studied after a single intravenous dose of 0.7 mg/kg body weight. Carprofen was administered to five clinically healthy cows and to the same cows 3 weeks later, 2 h after intramammary infusion of endotoxin. Mastitis developed in all endotoxin-infused quarters. The pharmacokinetic characteristics of carprofen in healthy cows were a small volume of distribution (0.09 l/kg), a relatively low systemic clearance (2.4 ml/h kg), and a long elimination half-life (30.7 h). In the mastitic cows, systemic clearance (1.4 ml/h kg) was significantly lower (P less than 0.01), and elimination half-life (43.0 h) was significantly longer (P less than 0.01) than in the normal animals. Concentrations of carprofen in milk from healthy quarters were below the limit of detection for the assay (0.022 micrograms/ml). In milk from mastitic quarters, concentrations of carprofen increased up to 0.164 micrograms/ml during the first 12 h after induction of mastitis, but were less than 0.022 micrograms/ml at 24 to 48 h. Compared with the untreated mastitic controls, carprofen treatment significantly reduced heart rate (P less than 0.01), rectal temperature (P less than 0.001), quarter swelling (P less than 0.01) and other parameters measured. Local and systemic adverse reactions to carprofen were not observed.

Pharmacokinetics of Pyridostigmine in Dogs

The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extendedrelease tablet, all at a level of ~0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h ± 2.1 SD), low systemic clearance (13 mL/min/kg ± 1 SD) and high volumes of distribution (Vdλz, 8.7 L/kg ± 1.9 SD and Vdss, 3.9 L/kg ± 0.9 SD). The ratio of mean residence times in tissues and plasma was >4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% ± 4.3 SD from the syrup and 33.6% ± 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.

Pharmacokinetics of propofol when given by intravenous infusion.

We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half-life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h-1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half-life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4-5 half-lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half-life of the drug. Therefore, the long elimination half-life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.

The Pharmacokinetics of Omeprazole in Humans—A Study of Single Intravenous and Oral Doses

The pharmacokinetics of omeprazole, hydroxyomeprazole, omeprazolesulfone, and "remaining metabolites" have been studied in eight young healthy subjects following an acute i.v. and oral dose of 10 and 20 mg of 14C-labeled drug, respectively. The oral dose was given as a buffered solution. Two subjects exhibited essentially higher and more sustained plasma levels of omeprazole than the others. This was due to a higher bioavailability, lower clearance, and longer t1/2 of omeprazole in these two subjects. Maximum concentration (0.7-4.6 mumol/L) was reached between 10 and 25 min after oral dosing. The median bioavailability was 39% (25-117%) and the median systemic plasma clearance was 624 ml/min (range of 59-828 ml/min). The corresponding t1/2 for the i.v. dose was 35 min (16-150 min) and 39 min (14-186 min) after oral administration. The drug was rapidly distributed to extravascular sites (mean t1/2 lambda 1 = 3.0 +/- 0.8 min). Mean Vss was 0.23 +/- 0.04 L/kg. Low systemic clearance of omeprazole was associated with a decreased formation rate of hydroxyomepraxole and "remaining metabolites" while omeprazolesulfone formation seemed to be less affected. However, there was a clear-cut correlation between the t1/2 of omeprazole and of its omeprazolesulfone metabolite, indicating that the elimination of these two compounds is mediated by the same isoenzyme. The mean urinary recovery of the radioactive dose during 96 h was 78.3 +/- 2.3 and 75.7 +/- 2.6% for the i.v. and oral dose, respectively. Insignificant amounts were due to unchanged drug and omeprazolesulfone. The excretion of hydroxyomeprazole during the first 12 h varied between 4.6 to 15.5% of a given dose. The mean recovery of radioactivity in the feces was 19.3 +/- 3.1% of a given i.v. dose and 18.2 +/- 2.3% when given orally. It is concluded that omeprazole is mainly eliminated metabolically and that there is a substantial interindividual variation in the rate of formation of primary and secondary metabolites. This variation in omeprazole disposition is probably of limited clinical importance. The half-life, with a maximum of approximately 3 h, is too short to cause accumulation when the drug is administered in a once-daily regimen.

Disposition of the Aldose Reductase Inhibitor AL01576 in Rats

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of ~30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the Gl tract. The highest radioactivity concentrations at 4 and 24 h were in the Gl tract, kidney, adrenals, and liver. At 168 h, the highest concentrations of radioactivity were found in the testes, kidneys, lungs, and adrenals, although the recovery from these four tissues combined represented <0.5% of the administered dose. After intravenous dosing, the recovery of radioactivity in the selected tissues (blood, liver, kidney, lung, brain, heart, spleen, testes, muscle, eyes, adrenals, skin, fat, and Gl tract) measured was 82, 75, 13, and 4% of the administered dose at 4, 24, 72, and 168 h, respectively. Overall, the data suggest that AL01576 is readily absorbed when administered orally, is distributed throughout the body tissues, is excreted predominantly by the feces through biliary excretion, and has a low systemic clearance and a long biologic half-life.